A High-Resolution Genetic Map for the Laboratory Rat

Littrell, John; Tsaih, Shirng‐Wern; Baud, Amelie; Rastas, Pasi; Solberg‐Woods, Leah; Flister, Michael J.

doi:10.1534/g3.118.200187

Cited by 21 publications

(10 citation statements)

References 22 publications

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“…Here, the Z-score is the number of standard deviations to reflect the amount of variability within a tested dataset. We used the SSLP marker information from the Rat Genome Database ( ) and the sex-averaged genetic map for rat genome assembly (rn6) ( Littrell et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Integrative genomic analysis of blood pressure and related phenotypes in rats

Takeuchi

Liang

Isono

et al. 2021

Disease Models &Amp; Mechanisms

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Despite remarkable progress made in human genome-wide association studies, there remains a substantial gap between statistical evidence for genetic associations and functional comprehension of the underlying mechanisms governing these associations. As a means of bridging this gap, we performed genomic analysis of blood pressure (BP) and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP), both of which are unique genetic models of severe hypertension and cardiovascular complications. By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n=1415), fine congenic mapping (maximum n=8704), pharmacological intervention and comparative analysis with transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY); e.g. inter-strain BP differences between SHRSP and WKY could be largely explained by an aggregate of BP changes in seven SHRSP-derived consomic strains. We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this study, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein–kinin/renin–angiotensin systems (KKS/RAS), in which the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogs. In combination with a pharmacological intervention, we provide in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, in a rat polygenic hypertension model.

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Section: Methodsmentioning

confidence: 99%

Integrative genomic analysis of blood pressure and related phenotypes in rats

Takeuchi

Liang

Isono

et al. 2021

Disease Models &Amp; Mechanisms

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“…LDSC is software designed to determine if observed inflation is due to cryptic relatedness and population stratification or true polygenic signal spread across regions of high LD [35]. Since there is no genetic map available for Sprague Dawley rats, we used a map created for heterogeneous stock (HS) rats [105], a similarly outbred population that shares some ancestry with SD. An LD window size of 5 centimorgans was used, corresponding to the point at which SD LD decayed sufficiently in most subgroups for loci to be considered unlinked.…”

Section: Methodsmentioning

confidence: 99%

Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies

Gileta

Fitzpatrick

Chitre

et al. 2018

Preprint

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30Sprague Dawley (SD) rats are one of the most commonly used outbred rat strains. Despite 31 this, the genetic characteristics of SD are poorly understood. We collected behavioral data from 32 4,625 SD rats acquired predominantly from two commercial vendors, Charles River Laboratories 33 and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we 34 obtained dense, high-quality genotypes at 234,887 SNPs across 4,061 rats. This genetic data 35 allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that 36 the two populations are highly diverged (FST > 0.4). We also used these data to perform a genome-37 wide association study (GWAS) of Pavlovian conditioned approach (PavCA), which assesses the 38 propensity for rats to attribute motivational value to discrete, reward-associated cues. Due to the 39 genetic divergence between rats from Charles River and Harlan, we performed two separate 40 GWAS by fitting a linear mixed model that accounted for within vendor population structure and 41 using meta-analysis to jointly analyze the two studies. We identified 18 independent loci that were 42 significantly associated with one or more metrics used to describe PavCA; we also identified 3 43 loci that were body weight, which was only measured in a subset of the rats. The genetic 44 characterization of SD rats is a valuable resource for the rat community that can be used to inform 45 future study design. 46 AuthorSummary 47 Outbred Sprague Dawley rats are among the most commonly used rats for neuroscience, 48 physiology and pharmacological research. SD rats are sold by several commercial vendors, 49 including Charles River Laboratories and Harlan Sprague Dawley Inc. (now Envigo). Despite their 50wide spread use, little is known about the genetic diversity of SD. We genotyped more than 4,000 51 2 SD rats, which we used to characterize genetic differences between SD rats from Charles River 52 Laboratories and Harlan. Our analysis revealed that the two SD colonies are highly divergent. We 53 also performed a genome-wide association study (GWAS) for Pavlovian conditioned approach 54 (PavCA), which assesses the propensity for rats to attribute motivational value to discrete, reward-55 associated cues. Our results demonstrate that, despite sharing an identical name, SD rats are 56 obtained from different vendors are genetically very different. We conclude that results obtained 57 using SD rats should not be presented without also carefully noting the vendor. 58 Introduction 59Rats are among the most commonly used organisms for experimental psychology and 60 biomedical research. Whereas research using mice makes extensive use of inbred strains, in rats, 61 it is more common to use commercially available outbred populations. Among the commercially 62 available outbred rat populations, the Sprague Dawley strain (SD) is one of the most widely used. 63SD rats are distributed by several vendors. Each vendor has multiple breeding locations, and each 64 breeding locatio...

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“…We also tested two types of linearly interpolated genetic maps, with recombination rates set at either 1cM/Mb or the chromosome specific averages for rats, as reported by Jensen-Seaman et al (Jensen-Seaman 2004). Lastly, late in the course of this project, we experimented with an HS-specific genetic map developed by Littrell et al (Littrell et al 2018).…”

Section: Genetic Mapsmentioning

confidence: 99%

“…All genetic maps performed similarly (Table S5). Surprisingly, the linear genetic maps performed just as well as the HS-specific map (Littrell et al 2018). Thus, for simplicity, we chose to use the chromosome-specific values initially published by Jensen-Seaman (Jensen-Seaman 2004).…”

Section: Variant Callingmentioning

confidence: 99%

Adapting Genotyping-by-Sequencing and Variant Calling for Heterogeneous Stock Rats

Gileta

Gao²,

Chitre³

et al. 2020

G3 Genes|Genomes|Genetics

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The heterogeneous stock (HS) is an outbred rat population derived from eight inbred rat strains. HS rats are ideally suited for genome wide association studies; however, only a few genotyping microarrays have ever been designed for rats and none of them are currently in production. To address the need for an efficient and cost effective method of genotyping HS rats, we have adapted genotype-by-sequencing (GBS) to obtain genotype information at large numbers of single nucleotide polymorphisms (SNPs). In this paper, we have outlined the laboratory and computational steps we took to optimize double digest genotype-by-sequencing (ddGBS) for use in rats. We evaluated multiple existing computational tools and explain the workflow we have used to call and impute over 3.7 million SNPs. We have also compared various rat genetic maps, which are necessary for imputation, including a recently developed map specific to the HS. Using our approach, we obtained concordance rates of 99% with data obtained using data from a genotyping array. The principles and computational pipeline that we describe could easily be adapted for use in other species for which reliable reference genome sets are available.

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A High-Resolution Genetic Map for the Laboratory Rat

Cited by 21 publications

References 22 publications

Integrative genomic analysis of blood pressure and related phenotypes in rats

Integrative genomic analysis of blood pressure and related phenotypes in rats

Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies

Adapting Genotyping-by-Sequencing and Variant Calling for Heterogeneous Stock Rats

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